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Tumor expression, plasma levels and genetic polymorphisms of the coagulation inhibitor TFPI are associated with clinicopathological parameters and survival in breast cancer, in contrast to the coagulation initiator TF

INTRODUCTION: Hypercoagulability in malignancy increases the risk of thrombosis, but is also involved in cancer progression. Experimental studies suggest that tissue factor (TF) and tissue factor pathway inhibitor (TFPI) are involved in cancer biology as a tumor- promoter and suppressor, respectivel...

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Autores principales: Tinholt, Mari, Vollan, Hans Kristian Moen, Sahlberg, Kristine Kleivi, Jernström, Sandra, Kaveh, Fatemeh, Lingjærde, Ole Christian, Kåresen, Rolf, Sauer, Torill, Kristensen, Vessela, Børresen-Dale, Anne-Lise, Sandset, Per Morten, Iversen, Nina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4423106/
https://www.ncbi.nlm.nih.gov/pubmed/25882602
http://dx.doi.org/10.1186/s13058-015-0548-5
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author Tinholt, Mari
Vollan, Hans Kristian Moen
Sahlberg, Kristine Kleivi
Jernström, Sandra
Kaveh, Fatemeh
Lingjærde, Ole Christian
Kåresen, Rolf
Sauer, Torill
Kristensen, Vessela
Børresen-Dale, Anne-Lise
Sandset, Per Morten
Iversen, Nina
author_facet Tinholt, Mari
Vollan, Hans Kristian Moen
Sahlberg, Kristine Kleivi
Jernström, Sandra
Kaveh, Fatemeh
Lingjærde, Ole Christian
Kåresen, Rolf
Sauer, Torill
Kristensen, Vessela
Børresen-Dale, Anne-Lise
Sandset, Per Morten
Iversen, Nina
author_sort Tinholt, Mari
collection PubMed
description INTRODUCTION: Hypercoagulability in malignancy increases the risk of thrombosis, but is also involved in cancer progression. Experimental studies suggest that tissue factor (TF) and tissue factor pathway inhibitor (TFPI) are involved in cancer biology as a tumor- promoter and suppressor, respectively, but the clinical significance is less clear. Here, we aimed to investigate the clinical relevance of TF and TFPI genetic and phenotypic diversity in breast cancer. METHODS: The relationship between tumor messenger RNA (mRNA) expression and plasma levels of TF and TFPI (α and β), tagging single nucleotide polymorphisms (tagSNPs) in F3 (TF) (n = 6) and TFPI (n = 18), and clinicopathological characteristics and molecular tumor subtypes were explored in 152 treatment naive breast cancer patients. The effect of tumor expressed TF and TFPIα and TFPIβ on survival was investigated in a merged breast cancer dataset of 1881 patients. RESULTS: Progesterone receptor negative patients had higher mRNA expression of total TFPI (α + β) (P = 0.021) and TFPIβ (P = 0.014) in tumors. TF mRNA expression was decreased in grade 3 tumors (P = 0.003). In plasma, total TFPI levels were decreased in patients with larger tumors (P = 0.013). SNP haplotypes of TFPI, but not TF, were associated with specific clinicopathological characteristics like tumor size (odds ratio (OR) 3.14, P = 0.004), triple negativity (OR 2.4, P = 0.004), lymph node spread (OR 3.34, P = 0.006), and basal-like (OR 2.3, P = 0.011) and luminal B (OR 3.5, P = 0.005) molecular tumor subtypes. Increased expression levels of TFPIα and TFPIβ in breast tumors were associated with better outcome in all tumor subtypes combined (P = 0.007 and P = 0.005) and in multiple subgroups, including lymph node positive subjects (P = 0.006 and P = 0.034). CONCLUSIONS: This study indicates that genetic and phenotypic variation of both TFPIα and TFPIβ, more than TF, are markers of cancer progression. Together with the previously demonstrated tumor suppressor effects of TFPI, the beneficial effect of tumor expressed TFPI on survival, renders TFPI as a potential anticancer agent, and the clinical significance of TFPI in cancer deserves further investigation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13058-015-0548-5) contains supplementary material, which is available to authorized users.
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spelling pubmed-44231062015-05-08 Tumor expression, plasma levels and genetic polymorphisms of the coagulation inhibitor TFPI are associated with clinicopathological parameters and survival in breast cancer, in contrast to the coagulation initiator TF Tinholt, Mari Vollan, Hans Kristian Moen Sahlberg, Kristine Kleivi Jernström, Sandra Kaveh, Fatemeh Lingjærde, Ole Christian Kåresen, Rolf Sauer, Torill Kristensen, Vessela Børresen-Dale, Anne-Lise Sandset, Per Morten Iversen, Nina Breast Cancer Res Research Article INTRODUCTION: Hypercoagulability in malignancy increases the risk of thrombosis, but is also involved in cancer progression. Experimental studies suggest that tissue factor (TF) and tissue factor pathway inhibitor (TFPI) are involved in cancer biology as a tumor- promoter and suppressor, respectively, but the clinical significance is less clear. Here, we aimed to investigate the clinical relevance of TF and TFPI genetic and phenotypic diversity in breast cancer. METHODS: The relationship between tumor messenger RNA (mRNA) expression and plasma levels of TF and TFPI (α and β), tagging single nucleotide polymorphisms (tagSNPs) in F3 (TF) (n = 6) and TFPI (n = 18), and clinicopathological characteristics and molecular tumor subtypes were explored in 152 treatment naive breast cancer patients. The effect of tumor expressed TF and TFPIα and TFPIβ on survival was investigated in a merged breast cancer dataset of 1881 patients. RESULTS: Progesterone receptor negative patients had higher mRNA expression of total TFPI (α + β) (P = 0.021) and TFPIβ (P = 0.014) in tumors. TF mRNA expression was decreased in grade 3 tumors (P = 0.003). In plasma, total TFPI levels were decreased in patients with larger tumors (P = 0.013). SNP haplotypes of TFPI, but not TF, were associated with specific clinicopathological characteristics like tumor size (odds ratio (OR) 3.14, P = 0.004), triple negativity (OR 2.4, P = 0.004), lymph node spread (OR 3.34, P = 0.006), and basal-like (OR 2.3, P = 0.011) and luminal B (OR 3.5, P = 0.005) molecular tumor subtypes. Increased expression levels of TFPIα and TFPIβ in breast tumors were associated with better outcome in all tumor subtypes combined (P = 0.007 and P = 0.005) and in multiple subgroups, including lymph node positive subjects (P = 0.006 and P = 0.034). CONCLUSIONS: This study indicates that genetic and phenotypic variation of both TFPIα and TFPIβ, more than TF, are markers of cancer progression. Together with the previously demonstrated tumor suppressor effects of TFPI, the beneficial effect of tumor expressed TFPI on survival, renders TFPI as a potential anticancer agent, and the clinical significance of TFPI in cancer deserves further investigation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13058-015-0548-5) contains supplementary material, which is available to authorized users. BioMed Central 2015-03-26 2015 /pmc/articles/PMC4423106/ /pubmed/25882602 http://dx.doi.org/10.1186/s13058-015-0548-5 Text en © Tinholt et al.; licensee BioMed Central. 2015 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Tinholt, Mari
Vollan, Hans Kristian Moen
Sahlberg, Kristine Kleivi
Jernström, Sandra
Kaveh, Fatemeh
Lingjærde, Ole Christian
Kåresen, Rolf
Sauer, Torill
Kristensen, Vessela
Børresen-Dale, Anne-Lise
Sandset, Per Morten
Iversen, Nina
Tumor expression, plasma levels and genetic polymorphisms of the coagulation inhibitor TFPI are associated with clinicopathological parameters and survival in breast cancer, in contrast to the coagulation initiator TF
title Tumor expression, plasma levels and genetic polymorphisms of the coagulation inhibitor TFPI are associated with clinicopathological parameters and survival in breast cancer, in contrast to the coagulation initiator TF
title_full Tumor expression, plasma levels and genetic polymorphisms of the coagulation inhibitor TFPI are associated with clinicopathological parameters and survival in breast cancer, in contrast to the coagulation initiator TF
title_fullStr Tumor expression, plasma levels and genetic polymorphisms of the coagulation inhibitor TFPI are associated with clinicopathological parameters and survival in breast cancer, in contrast to the coagulation initiator TF
title_full_unstemmed Tumor expression, plasma levels and genetic polymorphisms of the coagulation inhibitor TFPI are associated with clinicopathological parameters and survival in breast cancer, in contrast to the coagulation initiator TF
title_short Tumor expression, plasma levels and genetic polymorphisms of the coagulation inhibitor TFPI are associated with clinicopathological parameters and survival in breast cancer, in contrast to the coagulation initiator TF
title_sort tumor expression, plasma levels and genetic polymorphisms of the coagulation inhibitor tfpi are associated with clinicopathological parameters and survival in breast cancer, in contrast to the coagulation initiator tf
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4423106/
https://www.ncbi.nlm.nih.gov/pubmed/25882602
http://dx.doi.org/10.1186/s13058-015-0548-5
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